Abstract

The incidence of diet-induced metabolic disease has soared over the last half-century, despite national efforts to improve health through universal dietary recommendations. Studies comparing dietary patterns of populations with health outcomes have historically provided the basis for healthy diet recommendations. However, evidence that population-level diet responses are reliable indicators of responses across individuals is lacking. This study investigated how genetic differences influence health responses to several popular diets in mice, which are similar to humans in genetic composition and the propensity to develop metabolic disease, but enable precise genetic and environmental control. We designed four human-comparable mouse diets that are representative of those eaten by historical human populations. Across four genetically distinct inbred mouse strains, we compared the American diet's impact on metabolic health to three alternative diets (Mediterranean, Japanese, and Maasai/ketogenic). Furthermore, we investigated metabolomic and epigenetic alterations associated with diet response. Health effects of the diets were highly dependent on genetic background, demonstrating that individualized diet strategies improve health outcomes in mice. If similar genetic-dependent diet responses exist in humans, then a personalized, or "precision dietetics," approach to dietary recommendations may yield better health outcomes than the traditional one-size-fits-all approach.

KEYWORDS:

Diet ingredient profiles and geographic origins. (a) The purified control mouse diet, used for comparison to the American diet in our study, is typical of those used in mouse research. (b) Previous studies have evaluated metabolic effects using Western or high-fat diets. Instead, we designed human-comparable diets representative of the dietary patterns in human populations including: (c) a contemporary American diet, (d) a traditional Mediterranean diet, (e) a ketogenic diet analogous to the Maasai diet, and (f) a traditional Japanese diet.

Genetic-by-diet interactions in the methylation status of the Avpr1a locus and liver metabolome alterations. (a) B6 mice fed the American diet are hypermethylated relative to those fed the control mouse diet at the Avpr1a locus (n = 8), P < 0.0001 by Student’s t-test. (b) American diet feeding did not alter methylation status in the A strain (n = 7–8), P = 0.49 by Student’s t-test. (c) Transcript expression of Avpr1a was reduced by 84% in B6 mice fed the American diet relative to other strain-diet groups in mice fed diets for 6 months (n = 4–5), P < 0.0001 by ANOVA. (d) Transcript expression of Avpr1a is reduced by 54% in B6 mice fed the American diet for 2 weeks (n = 4), P = 0.0077 by Student’s t-test. (e) Number of liver metabolites, including both known and unknown, significantly altered by the American diet relative to the control mouse diet. (f) Proportion of metabolites significantly changed in all four strains (2%), three strains (4%), two strains (10%), or unique to one strain (84%). (g) Heatmap of effect sizes (Cohen’s d) for known metabolites significantly altered by the American diet relative to the control mouse diet across strains. * P < 0.05, ** P < 0.01, and *** P < 0.001 by ANOVA between means with Benjamin–Hochberg correction factor. A, A/J strain mice; B6, C57BL/6J strain mice; FVB, FVB/NJ strain mice; NOD, NOD/ShiLtJ strain mice.

Mean Health Scores for comparison of overall metabolic health of mice fed alternative diets relative to the American diet in each strain. The four health category scores () were averaged to provide a measure of overall metabolic health for each alternative diet relative to the American diet. A positive score represents improved health and a negative score represents diminished health. (a) Scores were calculated with body composition included and are shown with 95% C.I. or (b) are represented by a heat map. (c) Scores were also calculated without the body composition parameter and are shown with 95% C.I. or (d) are represented by a heat map. A, A/J strain mice; B6, C57BL/6J strain mice; FVB, FVB/NJ strain mice; NOD, NOD/ShiLtJ strain mice.